Project Background: Over the past decade, opioid use and injection drug use, particularly heroin injection, have increased across most US demographic groups, making opioid-use-related mortality and morbidity a public health crisis both for Veterans and non-Veterans. Morbidity from opioid use is broad, including acquisition of HIV and HCV, which spread efficiently through the transfer of blood in shared injecting equipment. Interventions to prevent morbidity from opioid use disorder include opioid agonist therapy, psychosocial interventions, HIV pre-exposure prophylaxis, clean needle programs, and enhanced testing for blood-borne diseases, but the cost effectiveness of these interventions in VA has not been determined. In prior work, we have evaluated the cost effectiveness of interventions to prevent HIV for people who inject drugs in non-Veteran populations and found some to be very expensive. Project Objectives: This study will assess health outcomes, costs, cost effectiveness, and budget impact of interventions to reduce the morbidity and mortality associated with opioid use disorder. The analysis will assess the cost effectiveness of interventions used individually or in combination when applied to populations of Veterans. Project Methods: To accomplish our objectives we will develop cost effectiveness models that assess health outcomes, cost, cost effectiveness, and budget impact of interventions to reduce morbidity and mortality from opioid use disorders. We will extend models that we have developed previously to reflect the costs and population characteristics of Veterans. Our analyses will include opioid agonist therapy, psychosocial interventions, HIV pre-exposure prophylaxis, use of naloxone, intensive screening for HIV and HCV, and other opioid use disorder treatments. To develop parameter estimates of effectiveness and harms of interventions, we will systematically review studies of interventions and assess study design, study quality, consistency, and applicability to Veteran populations. We will also assess whether comorbid conditions and receipt of social services affects the effectiveness of opioid use disorder treatment. To estimate costs of interventions we will use both literature-based estimates for interventions that VA has not provided and VA costs where available and appropriate. Our analyses will estimate both cost effectiveness and budget impact. Cost effectiveness is determined by the incremental benefit of an intervention compared to the next best alternative intervention divided by the incremental costs. Single interventions are unlikely to provide the same degree of benefit as combined interventions. However, how cost effectiveness varies for multiple interventions requires careful analyses because interventions may be synergistic or duplicative. Our analyses will account for these interdependencies. Our analyses will estimate deaths averted, adverse events from treatment, life years gained, quality-adjusted life years gained, cases of HIV or HCV averted (where appropriate), costs, and incremental cost effectiveness. Cost effectiveness provides insight into value and efficiency. However, even programs that are cost effective may require large total investments. Therefore, we will also estimate the budget impact of programs singly or in a portfolio. Budget impact captures the total expenditures that are required for implementation of programs at various levels of coverage or scale up. The study will provide an understanding of which interventions or combinations of interventions are likely to most improve the health of Veterans with opioid use disorder, along with estimates of the efficiency and total costs of the programs.